PURPOSE: Tribulus terrestris has been used as an aphrodisiac. However, little is known about the effects and mechanism of action of T. terrestris on penile erection. Therefore, the effect of a T. terrestris extract and the mechanism of action of the extract on relaxation of the corpus cavernosum (CC) were investigated. The erectogenic effects of an oral preparation of the extract were also assessed. MATERIALS AND METHODS: The relaxation effects and mechanism of action of the T. terrestris extract on rabbit CC were investigated in an organ bath. The intracavernous pressure (ICP) was calculated after oral administration of the extract for 1 month to evaluate whether the relaxation response of the CC shown in the organ bath occurred in vivo. Additionally, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were measured in the CC by immunoassay. Smooth muscle relaxation was expressed as the percentage decrease in precontraction induced by phenylephrine. The ICP was also assessed in rats after oral administration of the extract for 1 month, and changes in concentrations of cGMP and cAMP were monitored. RESULTS: Concentration-dependent relaxation effects of the extract on the CC were detected in the organ bath study. Relaxation of the CC by the T. terrestris extract was inhibited in both an endothelium-removed group and an L-arginen methyl ester pretreatment group. The ICP measured after oral administration of the T. terrestris extract for 1 month was higher than that measured in the control group, and a significant increase in cAMP was observed in the T. terrestris extract group. CONCLUSIONS: The T. terrestris extract induced concentration-dependent relaxation of the CC in an organ bath. The mechanism included a reaction involving the nitric oxide/nitric oxide synthase pathway and endothelium of the CC. Moreover, in an in vivo study, the T. terrestris extract showed a significant concentration-dependent increase in ICP. Accordingly, the T. terrestris extract may improve erectile function.
Adenosine Monophosphate ; Administration, Oral ; Animals ; Baths ; Endothelium ; Guanosine Monophosphate ; Immunoassay ; Male ; Muscle, Smooth ; Penile Erection ; Phenylephrine ; Rats ; Relaxation ; Tribulus

OBJECTIVE: Volume expansion has been known to be the major factor in the development of hypertenision in chronic hemodialysis(HD) patients. But some HD patients remain hypertensive even with adequate volume control, which suggests the role of undefined uremic toxin in the pathogenesis of hypertension. So we aimed to evaluate the status of blood pressure (BP) control and the effect of Kt/V (as a marker for removal of uremic toxin) on BP in chronic HD patients. METHODS: The status of BP control was obtained from records of 8 HD session in 132 patients in November 1996 and 127 patients in November 1997. Of 132 patients studied in 1996, 70 patients underwent a follow-up evaluation in 1997. All patients were dialyzed 3 times a week, 4 hours a session. Postdialytic cyclic 3',5' guanosine monophosphate (cGMP) level was measured in 48 patients as a marker of volume status. RESULTS: The prevalence of postdialytic hypertension (>140/90mmHg) was 73.5 in 1996 and 65.3% in 1997. Normotensive patients (postdialytic mean BP<114 mmHg) had higher Kt/V value than hypertensive patients in both 1996 and 1997. But there was no difference in the degree of ultrafiltration (UF) and cGMP level between two groups. Postdialytic mean BP was inversely correlated with Kt/V level but had no relationship with degree of UF and cGMP level in both 1996 and 1997. The group in which postdialytic mean BP had been decreased during 1 year study period had higher degree of elevation in Kt/V than the group in which postdialytic mean BP had been increased. The changes of postdialytic weight and degree of UF during study period were similar between two groups. The number of antihypertensives used were also inversely correlated with Kt/V but not correlated with degree of UF and cGMP level in both 1996 and 1997. CONCLUSION: Our study indicate that increasing HD adequacy is associated with improved control of postdialytic mean BP and less use of antihypertensive drugs. UF and antihypertensive drugs may not be adequate form of hypertension treatment as once thought and increasing HD adequacy can be an alternative method.
Antihypertensive Agents ; Blood Pressure* ; Dialysis* ; Follow-Up Studies ; Guanosine Monophosphate ; Humans ; Hypertension ; Prevalence ; Renal Dialysis* ; Ultrafiltration

Cyclic guanosine monophosphate adenosine monophosphate (cGAMP) synthase (cGAS) detects human immunodeficiency virus (HIV) and produces cGAMP to induce cytokines. Reverse transcribed DNA of HIV is critical for triggering innate immune responses as inhibitor of HIV reverse transcriptase blocked the induction of interferon-beta by the virus. Furthermore, knockout of cGAS in human or mouse cell lines abrogated the production of cytokines by HIV infection highlighting the essential role of cGAS in detection of HIV and other retroviruses.
Adenosine Monophosphate ; Animals ; Cell Line ; Cytokines ; DNA ; Guanosine Monophosphate ; HIV Infections ; HIV Reverse Transcriptase ; HIV* ; Humans ; Immunity, Innate ; Interferon-beta ; Mice ; Retroviridae

BACKGROUND: Cyclic guanosine monophosphate (cGMP) is involved in antinociception and vascular relaxation. The effects of zaprinast, which increases the level of cGMP by inhibiting phosphodiesterase, in the spinal cord have not been reported. The aims of this study were to evaluate the effects of intrathecal zaprinast on stimulus evoked by formalin injection, and to observe hemodynamic change in the absence of formalin stimulation. METHODS: Rats were implanted with lumbar intrathecal catheters. Intrathecal zaprinast was administered 10 min before formalin injection. After formalin injection, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. Mean arterial pressure (MAP) and heart rate (HR) were measured after intrathecal delivery of zaprinast for a period of 60 min. RESULTS: Intrathecal administration of zaprinast produced a dose-dependent suppression of flinches in both phases. Zaprinast had no evident effects on baseline MAP or HR. CONCLUSIONS: Zaprinast, a phosphodiesterase inhibitor, is active against the nociceptive state evoked by formalin stimulus without affecting resting MAP or HR. Accordingly, spinal zaprinast may be useful in the management of tissue-injury induced pain.
Animals ; Arterial Pressure ; Catheters ; Formaldehyde ; Guanosine Monophosphate ; Heart Rate ; Hemodynamics* ; Nociception* ; Pain Measurement ; Rats* ; Relaxation ; Spinal Cord*

Erectile dysfunction (ED) is a highly prevalent disorder that affects millions of men and considered to be an early symptom of atherosclerosis and a precursor of various systemic vascular disorders. The aim of the present study was to prepare ginsenoside Re enriched fraction (GS-F3K1, ginsenoside Re 10%, w/w) from ginseng berries flesh and to investigate the enhanced activities of GS-F3K1 on alcohol-induced ED. GS-F3K1 was prepared by the continuous liquid and solid separating centrifugation and circulatory ultrafiltration from ginseng berries flesh. GS-F3K1 was administered for 5 weeks in ethanol-induced ED rat by oral administration of 20% ethanol. To investigate the effects of GS-F3K1 on ED model, the levels of nitrite expression, cyclic guanosine monophosphate (cGMP) and erectile response of the penile corpus cavernosum of rat were measured. The erectile response of the corpus cavernosum was restored after GS-F3K1 administration, to a level similar to the normal group. The level of nitrite and cGMP expression in the corpus cavernosum of GS-F3K1-administered male rats was increased significantly compared to positive control group. GS-F3K1 from ginseng berries should effectively restore ethanol-induced ED in male rats and could be developed as a new functional food for the elderly men.
Administration, Oral ; Aged ; Animals ; Atherosclerosis ; Centrifugation ; Erectile Dysfunction* ; Ethanol ; Fruit* ; Functional Food ; Guanosine Monophosphate ; Humans ; Male ; Panax* ; Rats ; Ultrafiltration

BACKGROUND: Cyclic guanosine monophosphate (cGMP) plays an important role in the modulation of nociception. Although local sildenafil produces antinociception, by increasing cGMP through the inhibition of phosphodiesterase 5, the effect of spinal sildenafil has not been determined. The authors evaluated the effects of intrathecal sildenafil on the nociceptive behavior evoked by formalin injection and thermal stimulation. METHODS: Lumbar intrathecal catheters were implanted into rats, with formalin and Hot-Box tests used as nociceptive models. The formalin-induced nociceptive behavior (flinching response) and withdrawal latency to radiant heat were measured, and the general behaviors also observed. RESULTS: The intrathecal administration of sildenafil produced dose-dependent suppression of the flinches in both phases in the formalin test, and increased the withdrawal latency in the Hot-Box test. No abnormal behaviors were noted. CONCLUSIONS: Sildenafil, an inhibitor of phosphodiesterase 5, is active against the nociceptive state evoked in the spinal cord by formalin and thermal stimulations. Accordingly, spinal sildenafil may be useful in the management of pain.
Animals ; Catheters ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; Formaldehyde ; Guanosine Monophosphate ; Hot Temperature ; Nociception* ; Pain Measurement ; Rats* ; Spinal Cord ; Sildenafil Citrate

PURPOSE: To examine the association between phosphodiesterase type 5 (PDE5) inhibitor use and melanoma by 1) conducting a systematic review of observational studies; and 2) determining if low PDE5A gene expression in human melanoma correlated with decreased overall survival. MATERIALS AND METHODS: A systematic search of observational studies examining the association between PDE5 inhibitor use and melanoma was performed through ClinicalTrials.gov, the Cochrane Library, EMBASE, PubMed, and Web of Science databases, and seven eligible studies were identified. PDE5A gene expression was analyzed with RNA sequencing data from 471 human melanoma samples obtained from The Cancer Genome Atlas. RESULTS: Four studies reported a positive association between PDE5 inhibitor use and melanoma, and three studies found no correlation. RNA sequencing data analysis revealed that under-expression of the PDE5A gene did not impact clinical outcomes in melanoma. CONCLUSIONS: There is currently no evidence to suggest that PDE5 inhibition in patients causes increased risk for melanoma. The few observational studies that demonstrated a positive association between PDE5 inhibitor use and melanoma often failed to account for major confounders. Nonetheless, the substantial evidence implicating PDE5 inhibition in the cyclic guanosine monophosphate (cGMP)-mediated melanoma pathway warrants further investigation in the clinical setting.
Gene Expression ; Genome ; Guanosine Monophosphate ; Humans ; Melanoma ; Phosphodiesterase 5 Inhibitors ; Sequence Analysis, RNA ; Sildenafil Citrate ; Statistics as Topic ; Tadalafil ; Vardenafil Dihydrochloride

Tomato extract has been shown to exert antiplatelet activity in vitro and to change platelet function ex vivo, but with limitations. In this study, antiplatelet activity of water soluble tomato concentrate (Fruitflow I) and dry water soluble tomato concentrate (Fruitflow II) was investigated using rat platelets. Aggregation was induced by collagen and adenosine diphosphate and granule-secretion, [Ca2+]i, thromboxane B2, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels were examined. The activation of integrin αIIbβ3 and phosphorylation of signaling molecules, including mitogen-activated protein kinase (MAPK) and PI3K/Akt, were investigated by flow cytometry and immunoblotting, respectively. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were examined. Moreover, in vivo thrombus weight was tested by an arteriovenous shunt model. Fruitflow I and Fruitflow II significantly inhibited agonist induced platelet aggregation, adenosine triphosphate and serotonin release, [Ca2+]i, and thromboxane B2 concentration, while having no effect on cAMP and cGMP levels. Integrin αIIbβ3 activation was also significantly decreased. Moreover, both concentrates reduced phosphorylation of MAPK pathway factors such as ERK, JNK, P38, and PI3K/Akt. In vivo thrombus formation was also inhibited. Taken together, these concentrates have the potential for ethnomedicinal applications to prevent cardiovascular ailments and can be used as functional foods.
Adenosine Diphosphate ; Adenosine Monophosphate ; Adenosine Triphosphate ; Animals ; Blood Platelets* ; Cardiovascular Diseases ; Collagen ; Flow Cytometry ; Functional Food ; Guanosine Monophosphate ; Immunoblotting ; In Vitro Techniques ; Lycopersicon esculentum* ; Partial Thromboplastin Time ; Phosphorylation ; Platelet Aggregation ; Protein Kinases* ; Prothrombin Time ; Rats ; Serotonin ; Thrombosis ; Thromboxane B2 ; Water*

PURPOSE: Mycophenolic acid (MPA), a selective inhibitor of inosine monophosphate dehydrogenase (IMPDH), is the active metabolite of the immunosuppressive drug, mycophenolate mofetil (MMF). MMF is used to prevent an immune- mediate rejection response following organ transplantation via the inhibition of the IMPDH and GTP biosynthesis pathway. This study was designed to elucidate the mechanism by which MPA exerts its cytotoxic effect on human T lymphocytic and monocytic cell lines. METHODS: MOLT-4 and U937 cell lines were treated with MPA. Cell viability, expression of Bcl2 family proteins and Fas/Fas-L, effects of antioxidants and intracellular Ca2+ regulating agents and apoptosis were measured using a variety of microscopic and biochemical techniques. RESULTS: MPA induced the death of U937 and MOLT-4 cells in dose and time dependent manners, which was revealed an apoptosis with a characteristic ladder pattern of DNA fragmentation. In addition, BAPTA/AM, an intracellular Ca2+ chelator protected MOLT-4 cells from MPA treated apoptosis, although it did not have an additive with thapsigargin, and increases cytosolic Ca2+ stores. However, antioxidants including reduced glutathione (GSH) and N-acetyl-L-cysteine (NAC) did not inhibit the apoptosis of cells by MPA. Furthermore, guanosine suppressed MPA induced apoptosis of MOLT-4 lymphocytes, although adenosine did not. MPA also increased the catalytic activity of caspase family cysteine proteases including caspase-8, 9 and 3 proteases in MOLT-4 cells. Sequential activation indicated that the cleavage of caspase-8 and 9 precedes those of caspase-3. CONCLUSION: The results suggest that MPA induces the apoptotic death of MOLT-4 lymphocytes via the activations of caspase family proteases and the depletion of GTP.
Acetylcysteine ; Adenosine ; Antioxidants ; Apoptosis ; Caspase 3 ; Caspase 8 ; Cell Line ; Cell Survival ; Cysteine Proteases ; Cytosol ; DNA Fragmentation ; Glutathione ; Guanosine ; Guanosine Triphosphate ; Humans ; Inosine Monophosphate ; Lymphocytes ; Mycophenolic Acid* ; Organ Transplantation ; Oxidoreductases ; Peptide Hydrolases ; Signal Transduction* ; T-Lymphocytes* ; Thapsigargin ; Transplants ; U937 Cells

PURPOSE: The objective of this study was to evaluate the relaxant effect of scoparone from Artemisia capillaris on rabbit penile corpus cavernosum smooth muscle (PCCSM) and to elucidate the mechanism of action of scoparone for the treatment of erectile dysfunction (ED). MATERIALS AND METHODS: PCCSM that had been precontracted with phenylephrine was treated with 3 Artemisia herbs (A. princeps, A. capillaris, and A. iwayomogi) and 3 fractions (n-hexane, ethyl acetate, and n-butanol) with different concentrations (0.1, 0.5, 1.0, and 2.0 mg/mL). Four components (esculetin, scopoletin, capillarisin, and scoparone) isolated from A. capillaris were also evaluated. The PCCSM was preincubated with Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) and 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ). Cyclic nucleotides in the perfusate were measured by a radioimmunoassay. The interactions of scoparone with udenafil and rolipram were also evaluated. RESULTS: A. capillaris extract relaxed PCCSM in a concentration-dependent manner. Scoparone had the highest relaxant effect on PCCSM among the 4 components (esculetin, scopoletin, capillarisin, and scoparone) isolated from the ethyl acetate fraction. The application of scoparone on PCCSM pretreated with L-NAME and ODQ led to significantly less relaxation. Scoparone also increased the cyclic guanosine monophosphate (cGMP) levels in the perfusate in a concentration-dependent manner. Furthermore, scoparone enhanced udenafil- and rolipram-induced relaxation of the PCCSM. CONCLUSIONS: Scoparone relaxed the PCCSM mainly by activating the nitric oxide-cGMP signaling pathway, and it may be a new promising treatment for ED patients who do not completely respond to udenafil.
Artemisia* ; Coumarins ; Erectile Dysfunction ; Guanosine Monophosphate* ; Guanosine* ; Humans ; Male ; Muscle, Smooth ; NG-Nitroarginine Methyl Ester ; Nitric Oxide ; Nucleotides, Cyclic ; Penile Erection* ; Phenylephrine ; Phosphodiesterase 5 Inhibitors ; Radioimmunoassay ; Relaxation ; Rolipram ; Scopoletin